Cervical Cancer

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Introduction

Worldwide, cervical cancer is the second most common malignancy in women and is a major cause of morbidity and mortality.
Three out of four cases occur in developing countries.
The elderly, the economically disadvantaged, and those with poor healthcare access are all disproportionately
represented among women who develop and die from this disease. Approximately 80% of cervical cancers are squamous
cell carcinomas, and 15% are adenocarcinomas. Because of its association with human papilloma virus (HPV) infection,
as well as our improved ability to screen for premalignant stages of disease, cervical cancer is now a largely
preventable disease.

Epidemiology and Etiology

Incidence 11,150 new cases in the US estimated for 2007 [1]

Mortality rate of 3,670 estimated in the US for 2007, with most cases occurring in unscreened and suboptimally screened women [1, 2]

Etiology of cervical cancer linked with human papilloma virus (HPV), a double-stranded DNA virus that is sexually transmitted. HPV-16 and HPV-18 are the most commonly subtypes linked to cervical cancers and high-grade CINs.

Risk factors include young age at first intercourse, high number of sexual partners, high parity, cigarette smoking, race (African American women have 72% excess in incidence than Caucasian women[3]), low socioeconomic class, and immunosuppression

Screening Recommendations for Average-Risk Patients

The American Cancer Society recommends cervical cancer screening with Papanicolaou (PAP) tests starting approximately three years after the onset of vaginal intercourse and/or no later than twenty-one years of age [3].

Once cervical cancer screening has been initiated, it should be performed annually with conventional cytology or every two years with liquid-based cytology. When women reach 30 years of age and have had three consecutive, technically satisfactory tests with normal or negative results, they may be screened every two to three years unless they have additional risk factors.

Women over 70 years who are not at high risk may safely stop screening if they have had 3 or more documented normal results from technically satisfactory PAP smears, with no abnormal results within the past 10 years.[4]

Clinical Presentation

History: Cervical cancer is generally asymptomatic with effective screening. Occasionally, patients may complain of a heavier menstrual flow (menorrhagia), bleeding in between normal periods (metrorrhagia), post-coital bleeding, foul-smelling vaginal discharge, or pelvic pain. Anemia and its associated symptoms are frequently present. Less frequently, patients present with signs of advanced disease such as bowel obstruction and renal failure due to urinary tract obstruction.

Physical exam: Cervical lesions can be superficial ulcerations, exophytic tumors in the exocervix, or infiltration of the endocervix. The cervix and entire vagina should be carefully inspected and palpated to identify overt tumor or subepithelial vaginal extension. Rectovaginal examination permits the best assessment of tumor size and parametrial involvement. Palpation of the liver and inguinal and supraclavicular lymph nodes is important to screen for metastatic disease. Examination under anesthesia is often performed.

Diagnostic studies: Cystoscopy, proctoscopy, colposcopy, and hysteroscopy can be used to assess adjacent areas. Suspicious lesions should be confirmed by biopsy. IVP and chest x-ray are useful to evaluate for metastatic disease. Optional procedures including CT, MRI, PET, lymphangiography, and ultrasonography can be valuable for treatment planning for radiation or surgery, but cannot be used to assign disease stage in the FIGO classification (see below).

Natural Course and Pathology

Staging The International Federation of Gynecology and Obstetrics (FIGO) or the American Joint Commission (AJC) use primarily clinical staging systems based on histology for the early-stage cancers. For more advanced tumors, staging is based on extension of the disease in the pelvis.

Stage IA - microscopic cancer confined to the uterus

Stage IB - cancer visible by the naked eye confined to the uterus

Stage II - cervical cancer invading beyond the uterus but not to the pelvic wall or lower 1/3 of the vagina

Stage IVA - cervical cancer that invades the bladder or rectum, or extends beyond the pelvis

Stage IVB - distant metastases

Radiographic examination allowed under the FIGO staging includes chest x-ray and barium enema, as well as IV pyelography. However, where available, CT scanning or MRI is the preferred diagnostic study.

Surgical staging may reveal patients with microscopic disease in lymph nodes that can be treated with chemotherapy and potentially benefit in terms of long-term survival. However, the majority of patients who undergo it will be found not to have metastatic disease and will receive the same treatment as planned prior to surgical staging. The Gynecology Oncology Group (GOG) considers surgical staging to be optional for patients with advanced-stage cervical cancer.

Pathology 80% of cervical cancers are squamous cell, and 15% are adenocarcinomas [5]. Although patients with adenocarcinomas may have a worse prognosis due to a relatively higher frequency of late-stage diagnoses, outcomes appeared to be similar to that of squamous lesions when controlled for stage and tumor size.

Prognostic factors The most important prognostic factor remains clinical stage, defined by tumor volume and extent of disease spread. The overall 5-year survival rate ranges from 95% to 100% for patients with earliest stage cervical cancer, whereas patients with metastatic disease have a 5-year survival rate of less than 5 years after diagnosis [6]. Good prognostic factors include lesions less than 2 cm in diameter, superficially invasive, well-differentiated with no lymphovascular space involvement, positive surgical margins, and good general medical/nutritional status.

Intracavitary brachytherapy - Radioactive isotopes can be introduced directly into the uterine cavity and vaginal fornices with special applicators. In low-dose-rate (LDR) brachytherapy, the applicator is placed into the uterus while the patient is under anesthesia in the operating room, and the patient must stay in the hospital for 2-3 days during the procedure. High-dose-rate procedures can be performed on an outpatient basis. Several studies have cited comparable disease control and complication rates with either technique[6]. Used in Stage IIA or above.

External beam radiation therapy can be used in conjunction with intracavitary radiotherapy for patients with significant risk of pelvic lymph node involvement.

Chemotherapy alone does not produce a cure but has a role as adjuvant treatment for select patients. Due to the inability of many commonly used chemotherapeutic agents to effectively cross the blood-brain barrier, alternative agents and administration techniques must be employed for patients with brain tumors.

GOG phase III trial showed that concurrent chemo-RT patients who received cisplatin had higher rates of progression-free survival and overall survival than patients who received radiotherapy alone. Both groups had subsequent extrafascial hysterectomies 3-6 weeks after treatment [10]

Locally advanced disease (stage IIB- IVA)

Radiation

Advanced tumors require more external irradiation due to the inability of central radioisotope sources to effectively irradiate disease in the lateral parametrium.

Treatment aimed at pelvic control in advanced disease usually consists of radical chemoradiation (see below)

The superiority of concurrent platinum-based chemoradiation compared with radiation therapy alone has been confirmed in five phase III clinical trials, reducing the relative risk of death by 30-50% [10-14]